Effectiveness of Molnupiravir and Nirmatrelvir–Ritonavir in Hospitalized Patients With COVID-19
Authors: Eric Yuk Fai Wan, Vincent Ka Chun Yan, Anna Hoi Ying Mok, Ian Chi Kei Wong, Esther Wai Yin Chan
Journal: Annals of Internal Medicine (2023)

LettersOctober 2023Effectiveness of Molnupiravir and Nirmatrelvir–Ritonavir in Hospitalized Patients With COVID-19FREEEric Yuk Fai Wan, PhD*, Vincent Ka Chun Yan, BPharm*, Anna Hoi Ying Mok, MClinPharm*, Ian Chi Kei Wong, PhD, Esther Wai Yin Chan, PhDEric Yuk Fai Wan, PhD*Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Laboratory of Data Discovery for Health (D24H), Hong Kong Science and Technology Park, and Department of Family Medicine and Primary Care, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China, Vincent Ka Chun Yan, BPharm*Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China, Anna Hoi Ying Mok, MClinPharm*Department of Family Medicine and Primary Care, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China, Ian Chi Kei Wong, PhDCentre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Laboratory of Data Discovery for Health (D24H), Hong Kong Science and Technology Park, and Research Department of Practice and Policy, School of Pharmacy, University College London, London, United Kingdom, and Aston Pharmacy School, Aston University, Hong Kong, China, and London and Birmingham, United Kingdom, Esther Wai Yin Chan, PhDCentre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Laboratory of Data Discovery for Health (D24H), Hong Kong Science and Technology Park, Department of Pharmacy, The University of Hong Kong-Shenzhen Hospital, and The University of Hong Kong Shenzhen Institute of Research and Innovation, Hong Kong and Shenzhen, ChinaAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L23-0265 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail IN RESPONSE: We thank Drs. Focosi and Nicastri for their interest and would like to clarify several points.Drs. Focosi and Nicastri mentioned a potential conflict between our positive findings and the negative results from previous RCTs, such as MOVe-IN and EPIC-HOS. We believe that firm conclusions cannot be made from these preliminary data because both trials were terminated early. MOVe-IN was terminated after the phase 2 dose-ranging study, and EPIC-HOS was terminated early because of anticipated recruitment issues (1). Although early results of MOVe-IN showed no significant difference in recovery rates and all-cause mortality, the trial was conducted among unvaccinated persons during an Alpha wave (2). In contrast, our study was conducted during an Omicron wave with notably higher vaccination coverage. Our results differed from those reported in other RCTs; however, variations in transmission and severity of COVID-19 variants limit direct comparison.We appreciate concerns about potential biases that may account for the mortality hazard ratio observed. Our study used the cloning, censoring, and weighting approach whereby cloning assigns participants to treatment duration strategies at time zero, eliminating immortal time bias. Artificial censoring ensures that the clones follow their assigned strategy through follow-up. The selection bias introduced by this step is eliminated with inverse probability weighting (3). Because we explicitly specified and emulated a hypothetical randomized trial to answer the causal question in this study, fundamental errors in observational study design (such as inappropriately assigning time zero) that could result in erroneous causal conclusions were avoided (4).The prevalence rate of patients with at least 3 vaccine doses in our study was described as low. However, a considerable proportion of patients received 2 or more vaccine doses (3299 [48.8%] in the nirmatrelvir–ritonavir group and 5583 [33.9%] in the molnupiravir group). Our previous work reported that although 3 doses of vaccine offered the best protection, 2 doses also provided a reduction in COVID-19–related mortality (5). Of note, no interaction effect was found between drug treatments and the number of COVID-19 vaccine doses, suggesting that oral antivirals remain an effective treatment option regardless of vaccination status.Drs. Focosi and Nicastri also raised concerns about the representation of hospitalized patients with COVID-19. For example, 166 molnupiravir initiators vs. 1228 noninitiators and 95 nirmatrelvir–ritonavir initiators vs. 551 noninitiators received remdesivir during follow-up, and 32 molnupiravir initiators vs. 261 noninitiators and 11 nirmatrelvir–ritonavir initiators vs. 67 noninitiators received ventilatory support. Although the need for ventilatory support was low, underdiagnosis was possible because the outcome coding could have been affected by intensive care unit bed availability. Of note, the cumulative incidence of mortality in our study (17% in molnupiravir initiators vs. 19% in noninitiators and 8% in nirmatrelvir–ritonavir initiators vs. 10% in noninitiators) was much higher than that reported in MOVe-IN (5%) (2) but was comparable to that of 2 large studies that included hospitalized non–critically ill patients with COVID-19 (12% and 26%) (2), as well as that of a clinical trial for hospitalized adults treated with remdesivir (11% in the treatment group vs. 15% in the placebo group) (2). Therefore, our study population was representative of hospitalized patients with COVID-19.References1. Efficacy and safety of molnupiravir (MK-4482) in hospitalized adult participants with COVID-19 (MK-4482-001). ClinicalTrials.gov: NCT04575584. Accessed at https://classic.clinicaltrials.gov/ct2/show/NCT04575584 on 15 June 2023. Google Scholar2. Arribas JR, Bhagani S, Lobo SM, et al. Randomized trial of molnupiravir or placebo in patients hospitalized with COVID-19. NEJM Evid. 2022:1. doi:10.1056/EVIDoa2100044 CrossrefGoogle Scholar3. Hernán MA. How to estimate the effect of treatment duration on survival outcomes using observational data. BMJ. 2018;360:k182. [PMID: 29419381] doi:10.1136/bmj.k182 CrossrefMedlineGoogle Scholar4. Hernán MA. Methods of public health research—strengthening causal inference from observational data. N Engl J Med. 2021;385:1345-1348. [PMID: 34596980] doi:10.1056/NEJMp2113319 CrossrefMedlineGoogle Scholar5. Yan VKC, Wan EYF, Ye X, et al. Effectiveness of BNT162b2 and CoronaVac vaccinations against mortality and severe complications after SARS-CoV-2 Omicron BA.2 infection: a case-control study. Emerg Microbes Infect. 2022;11:2304-2314. [PMID: 35980089] doi:10.1080/22221751.r2022.2114854 CrossrefMedlineGoogle Scholar Comments 0 Comments Sign In to Submit A Comment Author, Article, and Disclosure InformationAuthors: Eric Yuk Fai Wan, PhD*; Vincent Ka Chun Yan, BPharm*; Anna Hoi Ying Mok, MClinPharm*; Ian Chi Kei Wong, PhD; Esther Wai Yin Chan, PhDAffiliations: Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Laboratory of Data Discovery for Health (D24H), Hong Kong Science and Technology Park, and Department of Family Medicine and Primary Care, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, ChinaCentre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, ChinaDepartment of Family Medicine and Primary Care, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, ChinaCentre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Laboratory of Data Discovery for Health (D24H), Hong Kong Science and Technology Park, and Research Department of Practice and Policy, School of Pharmacy, University College London, London, United Kingdom, and Aston Pharmacy School, Aston University, Hong Kong, China, and London and Birmingham, United KingdomCentre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Laboratory of Data Discovery for Health (D24H), Hong Kong Science and Technology Park, Department of Pharmacy, The University of Hong Kong-Shenzhen Hospital, and The University of Hong Kong Shenzhen Institute of Research and Innovation, Hong Kong and Shenzhen, China* Dr. Wan, Mr. Yan, and Ms. Mok were co–first authors and contributed equally to this work.Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M22-3057. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoEffectiveness of Molnupiravir and Nirmatrelvir–Ritonavir in Hospitalized Patients With COVID-19 Eric Yuk Fai Wan , Vincent Ka Chun Yan , Anna Hoi Ying Mok , Boyuan Wang , Wanchun Xu , Franco Wing Tak Cheng , Francisco Tsz Tsun Lai , Celine Sze Ling Chui , Xue Li , Carlos King Ho Wong , Philip Hei Li , Benjamin John Cowling , Ivan Fan Ngai Hung , Chak Sing Lau , Ian Chi Kei Wong , and Esther Wai Yin Chan Effectiveness of Molnupiravir and Nirmatrelvir–Ritonavir in Hospitalized Patients With COVID-19 Daniele Focosi , and Emanuele Nicastri Metrics October 2023Volume 176, Issue 10 Keywords Antivirals Clinical trials COVID-19 Hospitalizations Intensive care units Mortality Vaccines Ventilatory support ePublished: 17 October 2023 Issue Published: October 2023 Copyright & PermissionsCopyright © 2023 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...